One Doctor's Hopeful Plan To Eradicate Alzheimer's

“I hope I’m one thing worth not forgetting. Tell me that you’ll never let me go. When I can’t find the words that I’m trying to speak, when I don’t know the face in the mirror I see, when I feel I’m forgotten and lost in this world, won’t you please remember me?”~”Remember Me,” written by Chris Mann and Dr. Rudolph Tanzi along with Laura Mann, Willy Beaman and Dr. Dora Kovacs.

“I believe there is a significant possibility that we will have a solid plan for eradicating Alzheimer’s disease by 2025.”

The statement comes from Dr. Rudolph Tanzi, one of the foremost scientists behind curing the progressive, degenerative brain disease that the Alzheimer’s Association predicts will destroy the memories of some 14 million Americans by 2050.

, Neurogeneticist Dr. Rudolph Tanzi, the vice-chair of Neurology and director of the Genetics and Aging Research Unit at Massachusetts General Hospital. Tanzi, who serves as the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School, co-discovered all three early-onset familial Alzheimer’s disease genes and identified several others as leader of the Alzheimer’s Genome Project.(Photo Courtesy of Twin Cities PBS)

Not if he can help it. Tanzi said his new drug, developed with colleague Steve Wagner of the University of California San Diego (UCSD) and the National Institutes of Health (NIH) Blueprint Neurotherapeutics Network is getting ready for safety trials. The drug is called a “Gamma Secretase Modulator (GSM),” and Tanzi believes it will be at least a part of the prescription for stopping Alzheimer’s disease pathology from leading to symptoms. He said the GSM is expected to enter clinical safety trials with the National Institutes of Health (NIH) by the end of the year.

Tanzi said he fully expects doctors to be managing Alzheimer’s disease like they do heart disease by 2025, if not sooner.

GQ magazine named Tanzi a “Rock Star of Science.” After all, the neurogeneticist did play keyboards on Aerosmith’s last album and often jams with good friend Joe Perry, co-founder and lead guitarist of Aerosmith. But as Boston’s WBZ-TV reporter Paula Ebben put it, “it’s his work in his lab at Mass General Hospital that has rocked the world of Alzheimer’s research.”

LONDON, ENGLAND - JUNE 28: Steven Tyler and Joe Perry of Aerosmith performs on Day 1 of the Calling Festival at Clapham Common on June 28, 2014 in London, England. (Photo by Ben A. Pruchnie/Getty Images)

Tanzi has devoted his career to finding a cure for Alzheimer’s disease. He co-discovered all three early-onset familial Alzheimer’s disease genes in 1987 and 1995, and then identified several others as leader of the Alzheimer’s Genome Project supported by the Cure Alzheimer’s Fund. He is the vice-chair of Neurology and director of the Genetics and Aging Research Unit at Massachusetts General Hospital and serves as the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Tanzi also served on the team that was among the first to find a disease gene for Huntington’s disease, and he first discovered the Wilson's disease gene.

Tanzi has received the highest awards in his field, including the Metropolitan Life Foundation Award and Potamkin Prize. He’s published over 500 research papers and co-authored the popular trade books “Decoding Darkness,” New York Times Bestseller, “Super Brain” and “Super Genes.” Most recently, he received the 2015 Smithsonian American Ingenuity Award. In 2015, TIME magazine named him to its list of the 100 Most Influential People in the World.

Currently Alzheimer’s disease slowly destroys memory, thinking and eventually all ability to function. There are now over five million Americans with the disease in the United States alone. Worldwide, Tanzi said there are nearly 50 million. And with present-day methods, it’s not going to get any better.

“That 50 million is going to be what we have in this country if we don’t do something about this disease, because right now we’re treating the disease with drugs that temporarily affect the symptoms modestly—modest benefit for a short while,” Tanzi told an audience at a recent TEDx event, “Curing Alzheimer's with Science and Song” with acclaimed recording artist and actor, Chris Mann.

With a current projected lifespan of 80 years, “we’re living longer than ever. But the problem is our lifespan is outpacing our healthspan, especially the healthspan of our brains. All of the modern medicine has us living longer, but is our brain keeping up? That’s what we have to face right now,” Tanzi said.

But Tanzi isn’t giving up. Not by a long shot. He said we all have “a lot of reason to be optimistic” about finding a cure.

“I can tell you right now…the opportunity has never been greater to stop this disease in this generation, in our lifetime, maybe even by 2025,” Tanzi said, adding that dozens of Alzheimer’s genes have already been identified.

Tanzi said there are 71 million baby boomers heading toward risk age, deeming the crisis not only medical but financial. “Right now Alzheimer’s sucks up one in every five dollars of Medicare, and Medicaid,” he said.

At that rate, if estimates are correct, Tanzi said “Alzheimer’s Disease could single-handedly collapse our healthcare system.”

At the TEDx talk, Tanzi was later joined by chart-topping recording artist and actor Chris Mann for a performance of their anthem of hope, “Remember Me," that went viral when the two put it on social media as a means to raise awareness and promote the cure of Alzheimer’s. Mann lost two of his grandmothers from the rages of Alzheimer’s disease. One of them was diagnosed in her late forties. Mann said they wanted to show how terrifying it is to live with this disease. “When we posted our little passion project on Facebook and YouTube, it was sharing and being viewed at such a rapid pace that the live view counter could not keep up,” he said. Mann has performed over 700 times as The Phantom in "The Phantom of the Opera" and on NBC's "The Voice."

HOLLYWOOD, CA - JUNE 17: (L-R) Actors/singers Chris Mann, Katie Travis and Storm Lineberger arrive at the red carpet opening night of 'The Phantom of the Opera' at the Pantages Theatre on June 17, 2015 in Hollywood, California. (Photo by Chelsea Lauren/Getty Images for Hollywood Pantages)

More than 17 years of research went into developing the GSM, Tanzi said. He and colleague Dr. Doo Yeon Kim used Alzheimer’s disease genes to create a three- dimensional human stem cell-derived neural culture system (or simulated human brain organoid) that essentially replays the Alzheimer’s disease plaque and tangle processes—the ongoing pathology that scientists have proven leads to Alzheimer’s disease. Using this system, Tanzi developed a drug for Alzheimer’s disease including gamma secretase modulators and metal chaperones to lower beta-amyloid and tangle burden in the brain.

Tanzi calls it “Alzheimer’s-in-a-Dish.” Though the research is incredibly complex, scientists used stem cells to create human nerve cells. They then put them in a gel to simulate the human brain, and thus created full blown Alzheimer’s pathology in a Petri dish allowing them to have the first real view of the events that typically happen over decades—the formation of amyloid plaques that then lead to tangles and inflammation—in the brain, he said.

Alzheimer’s-in-a-Dish also solved the decades-old argument of whether the amyloid plaques or the tangles are to blame for Alzheimer’s disease, Tanzi said. “There is not a debate anymore,” he said. “All data say that if you keep the amyloid low, than you stop Alzheimer’s.”

(Photo courtesy of PhRMA)

The simulated human brain is in many ways superior to testing with mice which, because of their dissimilarity to human brains, did not tell scientists how the disease pathology progresses. When Tanzi discovered the first Alzheimer’s gene that is the precursor protein that makes the ingredients that are in the amyloid plaques, he finally had a window into the disease. But studies on mice did not tell the whole story, because the Alzheimer’s genes caused the mice to get plaques but not tangles, Tanzi said. “So scientists argued over whether plaques can really cause the disease.”

The mini human Alzheimer’s brain organoid first got plaques and later got the tangles which kill nerve cells. When Tanzi and his colleagues stopped the plaques with their GSM drug, there were no tangles. So Tanzi and colleagues provided the first definitive proof that the amyloid plaques cause the tangles. Yet, “Every Alzheimer trial that targeted amyloid plaques failed,” Tanzi said. “Brain imaging showed us that amyloid plaque build up is happening up to 10 to 20 years before any symptoms of dementia. So it doesn’t help them to lower the amyloid after the patient already has symptoms.”

Tanzi likens the situation to cancer and heart disease. “Unlike with heart disease and cancer, we don’t diagnose and treat Alzheimer’s disease until the symptoms hit, and then we treat the cause, the amyloid plaques. We needed to stop the amyloid plaques 10 to 20 years before the person shows symptoms.”

Tanzi said we can now determine the possibility of a person getting Alzheimer’s later in life using brain imaging and biomarkers when they are still asymptomatic, just like doctors do with cholesterol tests for heart disease. He said the time is not far in the future where blood tests will be available for Alzheimer’s as well.

“We need to lower the bar on clinical trials and find people with amyloid buildup on their brain early,” he said. “And then, if there is a safe drug that can reduce the plaques, we need to let these folks take it so that the plaque pathology does not lead to symptoms a decade or so later. Meanwhile expecting full blown Alzheimer’s patients to get better by hitting the plaques that started the disease decades ago is like trying to put out a forest fire by blowing out the match. We need the FDA to appreciate this important fact when it comes to clinical trials targeting plaques. If you treat a cancer patient with a 2-inch tumor that already led to organ failure, you would not expect much. Likewise, if you have heart disease in your family, you need to lower your cholesterol 10 to 20 years before you are symptomatic. We don’t wait until a patient suffers major heart attack with congestive heart disease to diagnose and treat with cholesterol lowering drugs.”

Until now, pharmaceutical companies have been testing drugs that slow down amyloid plaque formation in the brain by blocking the enzymes that produce the amyloid proteins: beta-secretase and gamma-secretase. The problem is that both of these enzymes have other important jobs such as cleaning out the old proteins from a brain nerve cell’s surface so it can remain healthy and functional. Scientists don’t want to block these important functions. The new drug called a GSM, being developed by Tanzi and Wagner, would target and regulate the gamma secretase so that it could still do its normal job, but when it comes to making amyloid, it would drive the production of shorter and thus safer amyloid proteins that are less prone to making brain plaques. Tanzi compares it to a cholesterol medicine that selectively lowers bad cholesterol without affecting the good.

Tanzi and Wagner expect their new GSM drug to go into safety trials with the NIH by the end of the year. If all goes well, he said it could be in trials with patients by the end of 2018. Those trials will likely be done at University of California San Diego (UCSD) and Massachusetts General Hospital (MGH).

Currently, brain imaging for amyloid plaques is possible but not covered by insurance since a positive diagnose is not considered “actionable.” In other words, the condition cannot be treated. But, if the GSM shows promise, “the ball will start to really roll”, Tanzi said. “If we have a drug that makes it actionable, a little white pill that’s cheap and safe, we can beat this”.

In the same way Americans now take a drug to prevent the buildup of cholesterol, Tanzi hopes that in the near future they will take one to bring their brain amyloid protein levels down. “Someday, once we have an effective and safe anti-amyloid drug, everyone will have their amyloid checked by 50 years old, let’s say, like they do with a colonoscopy. If you have a higher than normal amount, you can take a drug to prevent Alzheimer’s symptoms of dementia from occuring. By 2025, I think we’ll be there. If all goes swimmingly well, a GSM can be available in as little as five years.”

Tanzi said currently there are three classes of therapies for lowering amyloid levels in Alzheimer’s disease. They include: Beta-secretase (BACE) inhibitors, antibodies to amyloid (immunotherapy) and GSMs. “It could be one or a combination of any of these therapies. Maybe we have a cocktail of drugs or just the GSM. But that’s how we’re going to eradicate Alzheimer’s.” He added, “Based on safety efficacy, and price, I’m betting a GSM is going to win the day”.

This is good news for everyone, even seniors. “We can still help seniors if they don’t have symptoms,” Tanzi said. “There is still time to treat the amyloid.”

Robin Seaton Jefferson lives just outside of St. Louis with her husband of 24 years and two daughters. Find her on Twitter and Facebook @SeatonJefferson or contact her at rsjreporter@charter.net.

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